Germline mutations in a G protein identify signaling cross-talk in T cells.

Ham, Hyoungjun; Jing, Huie; Lamborn, Ian T; Kober, Megan M; Koval, Alexey; Berchiche, Yamina A; Anderson, D Eric; Druey, Kirk M; Mandl, Judith N; Isidor, Bertrand; Ferreira, Carlos R; Freeman, Alexandra F; Ganesan, Sundar; Karsak, Meliha; Mustillo, Peter J; Teo, Juliana; Zolkipli-Cunningham, Zarazuela; Chatron, Nicolas; Lecoquierre, François; Oler, Andrew J; Schmid, Jana Pachlopnik; Kuhns, Douglas B; Xu, Xuehua; Hauck, Fabian; Al-Herz, Waleed; Wagner, Matias; Terhal, Paulien A; Muurinen, Mari; Barlogis, Vincent; Cruz, Phillip; Danielson, Jeffrey; Stewart, Helen; Loid, Petra; Rading, Sebastian; Keren, Boris; Pfundt, Rolph; Zarember, Kol A; Vill, Katharina; Potocki, Lorraine; Olivier, Kenneth N; Lesca, Gaetan; Faivre, Laurence; Wong, Melanie; Puel, Anne; Chou, Janet; Tusseau, Maud; Moutsopoulos, Niki M; Matthews, Helen F; Simons, Cas; Taft, Ryan J; Soldatos, Ariane; Masle-Farquhar, Etienne; Pittaluga, Stefania; Brink, Robert; Fink, Danielle L; Kong, Heidi H; Kabat, Juraj; Kim, Woo Sung; Bierhals, Tatjana; Meguro, Kazuyuki; Hsu, Amy P; Gu, Jingwen; Stoddard, Jennifer; Banos-Pinero, Benito; Slack, Maria; Trivellin, Giampaolo; Mazel, Benoît; Soomann, Maarja; Li, Samuel; Watts, Val J; Stratakis, Constantine A; Rodriguez-Quevedo, Maria F; Bruel, Ange-Line; Lipsanen-Nyman, Marita; Saultier, Paul; Jain, Rashmi; Lehalle, Daphne; Torres, Daniel; Sullivan, Kathleen E; Barbarot, Sébastien; Neu, Axel; Duffourd, Yannis; Similuk, Morgan; McWalter, Kirsty; Blanc, Pierre; Bézieau, Stéphane; Jin, Tian; Geha, Raif S; Casanova, Jean-Laurent; Makitie, Outi M; Kubisch, Christian; Edery, Patrick; Christodoulou, John; Germain, Ronald N; Goodnow, Christopher C; Sakmar, Thomas P; Billadeau, Daniel D; Küry, Sébastien; Katanaev, Vladimir L; Zhang, Yu; Lenardo, Michael J; Su, Helen C     «

Ham, Hyoungjun; Jing, Huie; Lamborn, Ian T; Kober, Megan M; Koval, Alexey; Berchiche, Yamina A; Anderson, D Eric; Druey, Kirk M; Mandl, Judith N; Isidor, Bertrand; Ferreira, Carlos R; Freeman, Alexandra F; Ganesan, Sundar; Karsak, Meliha; Mustillo, Peter J; Teo, Juliana; Zolkipli-Cunningham, Zarazuela; Chatron, Nicolas; Lecoquierre, François; Oler, Andrew J; Schmid, Jana Pachlopnik; Kuhns, Douglas B; Xu, Xuehua; Hauck, Fabian; Al-Herz, Waleed; Wagner, Matias; Terhal, Paulien A; Muurinen, Mari; B...     »

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes Gαi2, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating Gαi2 mutations had clinical presentations that included impaired immunity. Mutant Gαi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant Gαi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation.      «

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2, which encodes Gαi2, a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating Gαi2 mutations had clinical presentations that included impaired immunity. Mutant Gαi2 impaired cell migration and aug...     »